Honokiol (HNK) is a natural extract of the leaves and root stems of the Magnolia plant that has long been used in traditional Asian medicine to treat thrombotic and gastrointestinal disorders. To determine if HNK has anti-inflammatory properties, we tested its effects in a mouse model of inflammatory rheumatoid arthritis (RA). Our initial studies show that both in vivo inflammation and disease progression and in vitro pro-inflammatory cytokine production and cellular activation were markedly inhibited, without increased cell death or in vivo toxicity. These preliminary findings suggest that HNK has promise in the treatment of chronic inflammatory diseases such as RA, which affects a large number of people. HNK also inhibited signaling via CD40, an immune receptor that has been implicated as playing a role in RA, as well as an EBV-encoded CD40 mimic called LMP1, that has been implicated in exacerbating autoimmune disease. Because HNK has multiple anti-inflammatory actions, it could prove more effective than treatments targeting a single molecule. Its long prior use in traditional medicine also suggests that it can be effective without dangerous side effects. This exploratory project will test the hypothesis that HNK will have effective anti-inflammatory properties in a mouse model of RA, and that its action will be exerted via interaction with GABA receptors to decrease production of pro-inflammatory cytokines. The first specific Aim will focus on optimizing anti-inflammatory effects in the mouse RA disease model, and the second Aim will examine the mechanism of action of HNK. PUBLIC HEALTH RELEVANCE: This project studies a natural plant product called Honokiol (HNK), which is extracted from plants of the species Magnolia, and has been used for many years as a traditional Asian medicine, without notable toxic side effects. Using controlled studies in a mouse model of human rheumatoid arthritis (RA), our initial work has shown that HNK can inhibit inflammation and progression of the disease. Interestingly, preliminary data indicate that HNK delivers signals to cells through a type of receptor of the nervous system. The current project seeks to build upon these studies to determine the optimal way to use HNK as a treatment for chronic inflammatory disease, and to better understand how HNK exerts its anti- inflammatory effects.